The proposed investigation will include the identification of the pathways of oxalate metabolism in man and other mammals and the extent of their contribution to endogenous oxalate biosynthesis. The key enzymes in each pathway will be isolated, purified, and characterized from human liver with particular emphasis being placed on substrate specificity and specific enzyme inhibitors. These will include (a) glycolic acid oxidase, the key enzyme in the synthesis of oxalate from glyoxylate, (b) D-amino acid oxidase, the key enzyme in the conversion of glycine to oxalate, (c) alcohol dehydrogenase, a key enzyme in the conversion of ethylene glycol to glyoxylate and oxalate, and (d) hydroxypyruvate decarboxylase, a key enzyme in the conversion of hydroxypyruvate to glyoxylate and oxalate. The most effective inhibitors for controlling oxalate synthesis in vitro will be identified and, through the use of isolated perfused rat liver and the intact rat, the most effective non-toxic inhibitors in vivo will be established. These regulators of oxalate synthesis will be evaluated for their effectiveness in the treatment and prevention of primary hyperoxaluria, ethylene glycol toxicity, kidney stone formation, and penthrane toxicity. A secondary, but related objective, is the elucidation of oxalate metabolism in man and other mammals. BIBLIOGRAPHIC REFERENCES: Chernoff, H. N. and Richardson, K. E. Effect of Phenylketonuria on Oxalate Synthesis. Clin. Chem. 21, 1026 (1975). Richardson, K.E. and Fry, D.W. Evidence for an Alternate Pathway of Oxalate Biosynthesis, in International Colloquium on Renal Lithiasis, 1975 (In Press).